Pathologic response
After four cycles of chemotherapy, an in-breast pCR (the primary endpoint) was demonstrated in 6 of 41 patients (15%). One of these six patients had residual DCIS and is listed separately. All of these patients had nodal pCR, whereas overall, 20 patients (49%) had negative nodes at resection.
The pathology reports of two patients were read as having invasive tumor within lymphatics and lymphovascular invasion (one each) with no measurable disease, with tumor thus sized as Tx. Neither of these patients had involved lymph nodes. Fourteen patients (34%) had MRD in the breast, and 8 of these 14 patients (57%) had residual nodal disease. Nine patients (22%) had T1c tumors (> 1–2 cm), with five of these nine patients (55%) having nodal disease. Seven patients (17%) had T2 tumors (> 2–5 cm) tumors, with five of these seven patients (71%) having nodal disease. These findings are summarized in Table 4. The correlation between in-breast cCR and pCR was 26%.
Biologic features of responders
Of interest, five of the six patients with a pCR had triple-negative tumors. This translates to a 22% pCR rate (5 of 23) in the triple-negative subset, and a pCR rate of 6% (1 of 18) in patients with ER-positive and/ or PR-positive tumors. The remaining patient with a pCR had ER-, PR-, and HER2-positive disease.
One patient had inflammatory breast cancer at diagnosis, and another developed this during the course of chemotherapy; the latter patient was removed from the study for progressive disease. Interestingly, the patient who presented with inflammatory breast cancer was one of the six patients with a pCR. Both of these inflammatory disease patients had triple-negative tumors.
Conversion to breast conservation
Breast conservation was offered to patients if it was deemed appropriate by the treating surgeon. Preoperative imaging was not mandated and thus was not routinely performed. Mastectomy was ultimately performed in 4 of the 6 patients (67%) with pCR and in 22 of the 35 patients (63%) with less than a pCR. Thus, the choice for breast conservation did not correlate well with response to chemotherapy.
Time to disease progression
At a median follow-up of 48 months (range, 7–63), 36 of 41 patients (88%) remained free of disease (range, 19–63 months). Two patients had progressive disease while they were on study treatment and had T3 tumors on resection. Another three patients were found to have progressive disease at 10, 41, and 50 months from study day 1.
Of the nine patients with T1c disease, only one patient (who had positive nodes at resection) had a recurrence (at 41 months). Overall, the patients who had a recurrence had MRD (one patient), T1c (one patient), T2 (one patient), and T3 (the same two patients whose disease progressed while they were on treatment and continued to progress after surgery).
Disease-free and overall survival
Three patients were lost to followup, with point of last contact at 19, 34, and 59 months. Of the 41 evaluable patients, 5 patients developed progressive disease, with 2 of these patients progressing during the study treatment. Disease-free survival at 12, 24, and 36 months was 89%, 89%, and 78%, respectively. Overall survival at these same time points was 95%, 90%, and 76%. None of the patients with a pCR is known to have recurrent disease. Of the six patients achieving pCR, two were lost to follow-up after 34 and 59 months, and four continued diseasefree at 38, 39, 55, and 62 months.
Adverse events
Five patients were removed from the study secondary to toxicities. Grade 3 and 4 toxicity events are summarized in Table 5. Grade 3 toxicities were anemia (4), diarrhea (2), epigastric pain (1), fatigue (2), hand-foot syndrome (1), infection (1), leukopenia (9), pain (5), and peripheral sensory neuropathy (1). Grade 4 toxicities were depression (1) and leukopenia (4). Toxicities (all grades) occurring in ≥ 10% of the 49 treated patients were anemia (76%), leukopenia (70%), fatigue (67%), nausea (59%), alopecia (49%), thrombocytopenia (47%), diarrhea (47%), constipation (37%), pain (35%), vomiting (31%), epigastric pain (27%), nail changes (22%), epiphora (22%), hand-foot syndrome (20%), infection (18%), edema (16%), rash (16%), anorexia (16%), and depression (10%). In the intent-to-treat population, there were nine dose reductions among nine patients, and 19 dose delays among 15 patients.
Discussion
The combination of agents tested thus far in the neoadjuvant setting consistently produce pCR rates far less than 50% in unselected populations. This study was begun prior to the widespread use of personalized medicine. Most prior published trials had utilized anthracycline-based chemotherapy, with response rates generally ranging between 7% and 36%.6,9–26,28–31,41,42